Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease

被引：27

作者：

Chen, Jian Jeffrey ^{[1
]}

Liu, Qingyian ^{[1
]}

Yuan, Chester ^{[1
]}

Gore, Vijay ^{[1
]}

Lopez, Patricia ^{[1
]}

Ma, Vu ^{[1
]}

Amegadzie, Albert ^{[1
]}

Qian, Wenyuan ^{[1
]}

Judd, Ted C. ^{[1
]}

Minatti, Ana E. ^{[1
]}

Brown, James ^{[1
]}

Cheng, Yuan ^{[1
]}

Xue, May ^{[1
]}

Zhong, Wenge ^{[1
]}

Dineen, Thomas A. ^{[7
]}

Epstein, Oleg ^{[7
]}

Human, Jason ^{[7
]}

Kreiman, Charles ^{[7
]}

Marx, Isaac ^{[7
]}

Weiss, Matthew M. ^{[7
]}

Hitchcock, Stephen A. ^{[1
]}

Powers, Timothy S. ^{[1
]}

Chen, Kui ^{[5
]}

Wen, Paul H. ^{[3
]}

Whittington, Douglas A. ^{[8
]}

Cheng, Alan C. ^{[8
]}

Bartberger, Michael D. ^{[2
]}

Hickman, Dean ^{[4
]}

Werner, Jonathan A. ^{[6
]}

Vargas, Hugo M. ^{[6
]}

Everds, Nancy E. ^{[6
]}

Vonderfecht, Steven L. ^{[6
]}

Dunn, Robert T., II ^{[6
]}

Wood, Stephen ^{[3
]}

Fremeau, Robert T., Jr. ^{[3
]}

White, Ryan D. ^{[7
]}

Patel, Vinod F. ^{[7
]}

机构：

[1] Amgen Inc, Dept Med Chem, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Mol Struct, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Neurosci, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Dept HTS & Mol Pharmacol, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA

[7] Amgen Inc, Dept Med Chem, Cambridge, MA 02142 USA

[8] Amgen Inc, Dept Mol Struct, Cambridge, MA 02142 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 04期

关键词：

Alzheimer's disease (AD); beta-Secretase (BACE1); Aminooxazoline; Xanthene; 3-Azaxanthene; Amyloid; A beta peptides; AMYLOID PRECURSOR PROTEIN; ENZYME BACE1 INHIBITORS; DESIGN; HYPOTHESIS; SERIES;

D O I：

10.1016/j.bmcl.2014.12.092

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

The beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure-and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Ab levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：767 / 774

页数：8

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